The adhesion of mammalian cells to the extracellular matrix is of fundamental importance in regulating growth, adhesion, motility and the development of proper cellular phenotype. This has implications for normal development, wound healing, immunity, chronic inflammatory diseases, and tumor metastasis. Evidence accumulated over the last several years suggests that the molecular basis for the adhesion of both normal and transformed cells is complex and probably involves several distinct cell surface molecules. Extracellular matrices consist of three types of macromolecules: collagens, proteoglycans and noncollagenous glycoproteins. The extracellular matrix molecule which has been most intensively studied with regard to cell adhesion is the noncollagenous cell adhesion glycoprotein, fibronectin, which is present in plasma, cell matrices, basal lamina and on cell surfaces. The fibronectin from plasma consists of a disulfide-bonded dimer having a molecular weight of 450,000 daltons. The two subunit chains ("A" and "B"), each of about 220,000 daltons, are observed under reducing conditions. This form of fibronectin will be referred to as "fibronectin" hereinafter.
Polypeptides from a 33 kD carboxyl terminal heparin-binding fragment of the A subunit fibronectin which promote adhesion and spreading of endothelial cells and melanoma cells are described in U.S. Pat. Nos. 4,839,464 and 5,019,646. The synthetic polypeptides corresponding to fibronectin residues described in these patents are disclosed as useful to (a) assist in nerve regeneration, (b) promote wound healing and implant acceptance, (c) promote cellular attachment to culture substrata, and (d) inhibit metastasis of malignant cells.
Evolution of inflammatory and immune reactions is dependent upon the recruitment and migration of circulating leukocytes to sites of injury or antigen deposition. The accumulation of leukocytes is dependent not only on chemotactic signals emanating from the inflammatory site, but also on cell-cell and cell-matrix interactions. Many of these cellular and matrix interactions are dependent upon expression of cell surface adhesion molecules (CAMs) [integrins, cell surface proteoglycans, selectins, etc.] which facilitate targeting and retention of circulating cells to sites of immunologic challenge [T. Springer, Nature, 346: 425-434 (1990); S. M. Albeda et al., FASEB J., 4: 2668-2680 (1990); Ruoslahti, J. Clin. Invest., 87: 1-5 (1991)].
Integrins represent a family of cell surface .alpha..beta. heterodimeric proteins that mediate cell adhesion to other cells and to extracellular matrix constituents, including fibronectin. Although the role of integrins and other CAMs in mediating arrest and adhesion of inflammatory cells prior to extravasation is complex and poorly understood, emerging evidence suggests that integrins may be pivotal in these events. Therefore, a need exists for a method employing an agent that inhibits or modulates emigration of circulating cells to the site of immunologic challenge as a mechanism to regulate inflammation and its associated disorders.